This application was filed under 35 U.S.C. 371, and is the U.S. national stage of PCT/KR00/00906, filed Aug. 16, 2000.
The present invention relates to novel fungicidal compounds having a fluorovinyl- or fluoropropenyl-oxyphenyloxime moiety, a process for preparing same and a fungicidal composition containing same as an active ingredient.
A number of fungicidal compounds have been in practical use to protect crops from various pathogenic fungi; and they may be classified into several groups according to their similar structural features. However, the repetitive use of a fungicide over a long period induces the appearance of new fungal strains resistant not only to the particular fungicide but also to related fungicides having common structural features. For this reason, continuous efforts have been undertaken to develop novel fungicides.
Such efforts have led to the development of new fungicides, e.g., propenoic esters derived from strobilurin (U.S. Pat. No. 4,994,495; WO 94/19331; U.S. Pat. No. 5,003,101) and other propenoic ester fungicides disclosed in EP A 0 278 595 (Zeneca), EP A 0 782 982 (Novatis), WO 96/33164 (Ciba-Geigy), WO 96/33164 (Rhone-Poulenc Agro), WO 98/56774 (BASF), WO 99/06379 (BASF), WO 99/23066 (Agrevo UK), German Patent Nos. 724,200 and 732,846 (both BASF), and British Patent No. 22,893 (Agrevo UK). However, these propenoic ester derivatives still have the problem of limited fungicidal activity.
Accordingly, it is a primary object of the present invention to provide a novel compound having a high fungicidal activity against a wide spectrum of plant pathogenic fungi.
It is another object of the present invention to provide a process for the preparation of said compound.
It is a further object of the present invention to provide a fungicidal composition containing said compound.
In accordance with one aspect of the present invention, there are provided a novel compound of formula (I) and stereoisomers thereof: 
wherein,
X is CH or N;
Y is O or NH;
R1 is hydrogen, C1-4 alkyl, or halogen-substituted C1-4 alkyl;
R2 is a phenyl group optionally carrying one or more substituents selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, methylenedioxy and halogen; or a naphthyl group; and
R3 is hydrogen or CF3.
The structure of the compound of formula (I) of the present invention is characterized by the fluorovinyl- or fluoropropenyl-oxyphenyloxime moiety, and depending on whether X is CH or N, it may also be classified as a propenoic acid derivative (X=CH) or as an iminophenylacetic acid derivative (X=N).
Among the compounds of the present invention, preferred are those wherein R1 is hydrogen or methyl, and R2 is phenyl group, or Cl- or F-substituted phenyl group.
The compound of formula (I) of the present invention may be prepared, as shown in Reaction Scheme A: 
wherein, X, R1, R2 and R3 have the same meanings as defined in formula (I) above.
In Reaction Scheme A, the compound of formula (I-a), i.e., a compound of formula (I) wherein Y is O, may be prepared by the steps of (a) reacting a compound of formula (II) with an oxime derivative of formula (III) in the presence of a base to obtain a compound of formula (IV); (b) debenzylating the compound of formula (IV) by hydrogenolysis in the presence of a Pd(C) catalyst to obtain a compound of formula (V-a); and (c) reacting the compound of formula (V-a) with a compound of formula (VI) in the presence of a base:
The compound of formula (II) is inclusive of the compounds of formula (II-a) (X=CH) and formula (II-b) (X=N): 
The compound of formula (II-a) may be prepared by esterification, formylation, methylation and bromination of o-tolylacetic acid according to a conventional method (Yamada, K. et al., Tetrahedron Lett., 2745(1973); Vyas, G. N. et al., Org. Syn. Coll., 4, 836(1963); Kalir, A., Org. Syn. Coll., 5, 825(1973); Korean Unexamined Patent Publication Nos. 98-83587 and 99-15785; and World Patent Publication No. WO 99/07665), as shown in Reaction Scheme B: 
The compound of formula (II-b) may be prepared by Grignard reaction, oxalylation, condensation, methylation and bromination of o-bromotoluene according to a conventional method (Rambaud, M. et al., Synthesis, 564(1988); Korean Unexamined Patent Publication Nos. 98-83587 and 99-15785; and World Patent Publication No. WO 99/07665), as shown in Reaction Scheme C: 
The compound of formula (III), on the other hand, represents, among others, the compounds of formula (III-a) (R1=H), formula (III-b) (R1=CH3) and formula (III-c) (R1=CF3): 
The compounds of formulas (III-a), (III-b) and (III-c) may be prepared by the steps of benzylation and condensation of 3-hydroxybenzaldehyde, 3-hydroxyacetophenone and 3-hydroxy-2xe2x80x22xe2x80x22xe2x80x2-trifluoroacetophenone, respectively, in accordance with a conventional method (Kuhn, R. et al., Chem. Ber. 90, 203(1957); Fletcher, H. G. et al., Methods Carbohydr. Chem., II, 166(1963); Freedman, H. H., et al., Tetrahedron Lett., 3251(1975); Lichtenhaler, F. W., et al., Tetrahedron Lett., 1425(1980); and Sugg, E. E., et al., J. Org. Chem., 50, 5032(1985)), as shown in Reaction Scheme D: 
wherein, R1 has the same meanings as defined in formula (I) above.
In the reaction to prepare the compound of formula (IV), the compound of formula (II) and the compound of formula (III) may be used in equimolar amounts and the base may be used in one or two equivalent amounts. The base may be an inorganic base, e.g., sodium hydride, potassium t-butoxide, sodium carbonate or potassium carbonate; or an organic base, e.g., triethyl amine or pyridine. The solvent which may be used in the reaction includes acetone, methyl ethyl ketone, benzene, toluene, tetrahydrofuran, acetonitrile, dichloromethane or dimethyl formamide, and the reaction may be conducted at a temperature ranging from room temperature to 100xc2x0 C. The progress of the reaction is conveniently followed by measuring the disappearance of the compound of formula (II) with thin layer chromatography (TLC).
Examples of the compound of formula (IV) include the compounds of formulas (IV-a) (X=CH, R1=H), (IV-b) (X=CH, R1=CH3), (IV-c) (X=CH, R1=CF3), (IV-d) (X=N, R1=H), (IV-e) (X=N, R1=CH3) and (IV-f) (X=N, R1=CF3), depending on the starting materials used, i.e., depending on any one of the reactions of the compound of formula (II-a) or (II-b) with the compound of formula (III-a), (III-b) or (III-c): 
Subsequently, the compound of formula (IV) is debenzylated by hydrogenolysis to obtain a phenolic ester compound of formula (V-a): 
wherein, X and R1 has the same meanings as defined previously.
Examples of the compound of formula (V-a) include the compounds of formulas (V-a-1) (X=CH, R1=H), (V-a-2) (X=CH, R1=CH3), (V-a-3) (X=CH, R1=CF3), (V-a-4) (X=N, R1=H), (V-a-5) (X=N, R1=CH3) and (V-a-6) (X=N, R1=CF3), which correspond 10 to the compounds of formulas (IV-a) to (IV-f), respectively: 
On the other hand, the compound of formula (VI) is inclusive of a compound of formula (VI-a), i.e., the compound of formula (VI) wherein R3 is H, and a compound of formula (VI-b), i.e., the compound of formula (I) wherein R3 is CF3. 
The compound of formula (VI-a) may be prepared by a Grignard reaction, reduction, halogenation and dehalogenation of a halide of R2 according to a conventional method (Herkes, F. E. et al., J. Org. Chem., 32, 1311(1967); and Nemeth, G. et al., J. fluorine Chem., 76, 91(1996)), as shown in Reaction Scheme E: 
wherein, R2 has the same meaning as defined in formula (I) above; and Z represents Cl or F.
Further, a compound of formula (VI-b) may be prepared by a Grignard reaction and Wittig reaction of a halide of R2 according to a conventional method (Herkes, F. E. et al., J. Org. Chem., 32, 1311(1967); and Wheatman. G. A. et al., J. Org Chem., 48, 917(1983)), as shown in Reaction Scheme F: 
wherein, R2 and Z have the same meanings as above.
In the step to prepare the compound of formula (I-a) of the present invention by reacting the compound of formula (V-a) with a compound of formula (VI) in the presence of a base, the compounds of formulas (V-a) and (VI) may be used in equimolar amounts and the base may be used in one to two equivalent amounts. The base may be an inorganic base, e.g., sodium hydride, potassium t-butoxide, sodium carbonate or potassium carbonate; or an organic base, e.g., triethyl amine or pyridine. The solvent, which may be used in the reaction, is benzene, toluene, tetrahydrofuran, acetonitrile, dichloromethane or dimethyl formamide, and the reaction temperature in the range of room temperature to 100xc2x0 C.
In the preparation of the compound of formula (I-b) by reacting the phenolic ester compound of formula (V-a) with methylamine to obtain a phenolic amide compound of formula (V-b), in a conventional manner, and then reacting the compound of formula (V-b) with a compound of formula (VI) in the presence of a base, methylamine may be preferably employed in an excess amount than the phenolic ester compound used. The above reaction may be conducted in the presence of an alcohol (e.g., methanol), acetonitrile, dichloromethane and dimethyl formamide, at a temperature ranging from room temperature to the boiling point of the solvent used.
Examples of the compound of formula (V-b) are the compounds of formulas (V-b-1) (X=CH, R1=H), (V-b-2) (X=CH, R1=CH3), (V-b-3) (X=CH, R1=CF3), (V-b-4) (X=N, R1=H), (V-b-5) (X=N, R1=CH3) and (V-b-6) (X=N, R1=CF3), which correspond to the compounds of formulas (IV-a) to (IV-f), respectively: 
On the other hand, the compound of formula (I-a) may be prepared, as shown in the above Reaction Scheme A, by reacting a compound of formula (II) with a compound of formula (VII) in the presence of a base. At this time, the compound of formula (II) and the compound of formula (VII) may be used in equimolar amounts and the base may be used in one or two equivalent amounts. The base may be an inorganic base, e.g., sodium hydride, potassium t-butoxide, sodium carbonate or potassium carbonate; or an organic base, e.g., triethylamine or pyridine. The solvent which may be used in the reaction includes acetone, methyl ethyl ketone, benzene, toluene, tetrahydrofuran, acetonitrile, dichloromethane or dimethyl formamide, and the reaction may be conducted at a temperature ranging from room temperature to 100xc2x0 C. The progress of the reaction is conveniently followed by measuring the disappearance of the compound of formula (II) with thin layer chromatography (TLC).
Further, the compound of formula (I-b) may be obtained by reacting the compound of formula (I-a) with methylamine in a conventional manner.
The compound of formula (VII) may be prepared by reaction of 3-hydroxybenzaldehyde, 3-hydroxyacetophenone or 3-hydroxy-2xe2x80x22xe2x80x22xe2x80x2-trifluoroacetophenone with a compound of formula (VI) to obtain a compound of formula (VIII) and condensation of the compound of formula (VIII) with hydroxylamine according to a conventional method (Lichtenhaler, F. W., et al., Tetrahedron Lett., 1425(1980); and Sugg, E. E., et al., J. Org. Chem., 50, 5032(1985)), as shown in Reaction Scheme G: 
wherein, R1, R2 and R3 have the same meanings as defined in formula (I).
The compound of formula (VII) is inclusive of a compound of formula (VII-a), i.e., the compound of formula (VII) wherein R3 is H, and a compound of formula (VII-b), i.e., the compound of formula (VII) wherein R3 is CF3, which correspond to the compounds of formulas (VI-a) and (VI-b) used as a starting material, respectively: 
The compound of formula (I) of the present invention has three double bonds, and when one ignores the double bond of the bridging oxime group, there exist four stereoisomers thereof, which, according to the terminology defined in the Cahn-Ingold-Prelog system (J. March, Advanced Organic Chemistry, 3rd Ed., Wiley-Interscience), may be expressed as (E,E), (E,Z), (Z,E) and (Z,Z) isomers. which are included within the scope of the present invention. 
(when R3 is H, (E,Z) isomer; and when R3 is CF3, (E,E) isomer) 
(when R3 is H, (E,E) isomer; and when R3 is CF3, (E,Z) isomer) 
(when R3 is H, (Z,Z) isomer; and when R3 is CF3, (Z,E) isomer) 
(when R3 is H, (Z,E) isomer; and when R3 is CF3, (Z,Z) isomer)
wherein, X, Y, R1, R2 and R3 have the same meanings as defined above.
In case a mixture of the E and Z isomers of the compound of formula (II) is used in the reaction shown in Reaction Scheme A, the compound of the present invention is obtained as a mixture of the above four isomers wherein the (E,E) and (E,Z) isomers predominate with minor amounts of the (Z,E) and (Z,Z) isomers.
However, in case only the E isomer of the compound of formula (II-a-4) or (II-b-4) is used, the compound of formula (I) of the present invention is obtained as a mixture of the (E,E ) and (E,Z) isomers, as is confirmed by 1H-NMR or 19F-NMR analysis.
According to the 1H-NMR analysis (reference compound, TMS) of the compound of formula (I) of the present invention wherein R3 is hydrogen, a hydrogen of vinyl group of (E,E) isomer is shown as a doublet having a coupling constant of 5 to 6 Hz at 5.5 to 5.8 ppm, while that of (E,Z) isomer is represented as a doublet having a coupling constant of 30 Hz at 5.0 to 5.4 ppm. The ratio of the (E,E) isomer to (E,Z) isomer is about 2:1 which may be calculated from integration on the 1H-NMR spectroscopy. This result can be confirmed by the 19F-NMR analysis. The 19F-NMR analysis of the compound (I) of the present invention wherein R3 is hydrogen, the fluorine substituent on the vinyl group of the (E,E) isomer is shown as a doublet having a coupling constant of 5.5 Hz at xe2x88x9283.3 ppm, while that of the (E,Z) isomer is represented by a doublet having a coupling constant of 28.6 Hz at xe2x88x9283.1 ppm; and, the (E,E) to (E,Z) isomer ratio is also confirmed to be about 2:1 from integration on the 19F-NMR spectroscopy.
According to the 19F-NMR analysis data of the compound of formula (I) of the present invention wherein R3 is CF3, the vinyl fluorine and the fluorine of CF3 of the (E,E) isomer are, respectively, a quartet having a coupling constant of 12.2 Hz at xe2x88x9275.9 ppm and a doublet having a coupling constant of 12.3 Hz at xe2x88x9258.7 ppm, while those of the (E,Z) isomer are, respectively, a quartet having a coupling constant of 23.9 Hz at xe2x88x9276.3 ppm and a doublet having a coupling constant of 24.7 Hz at xe2x88x9258.5 ppm. The (E,E) to (E,Z) isomer ratio is about 1:2 based on the integration of fluorine peaks.
The compound of the present invention has a broad spectrum of fungicidal activity against various plant pathogenic fungus, e.g. Pyricularia oryzae Carvara KA301 which causes Rice Blast, Rhizoctonia solani AG-1 which causes Rice Sheath Blight, Botrytis cinerae which causes Cucumber Gray Mold Rot, Phytophthora infestans which causes Tomato Late Blight, Puccinia recondita which causes Wheat Leaf Rust and Erysiphe graminis which causes Barley Powdery Mildew.
Accordingly, the present invention also includes within its scope fungicidal compositions comprising one or more of the compounds of formula (I) or stereoisomer thereof as an active ingredient, in association with fungicidally acceptable carriers.
The fungicidal compositions of the invention may be formulated in various forms such as an emulsion, aqueous dispersion, powder and granules which may contain conventional additives. The compound of the formula (I) may be used in an amount of 10 to 90% on the basis of the weight of an emulsion or aqueous dispersion, and 0.1 to 10% on the basis of the weight of granules.
Fungicidally acceptable carrier that may be used in the present invention is a liquid carrier, e.g., water, an alcohol(ethanol, ethylene glycol, glycerine), ketone(acetone, methylethylketone), ether(dioxane, tetrahydrofuran, cellosolve), aliphatic hydrocarbon(gasoline, Kerosene), halogenated hydrocarbon(chloroform, carbon tetrachloride), amide(dimethylformamide), ester(ethyl acetate, butyl acetate, fatty glycerine ester) and acetonitrile; and a solid carrier, e.g., mineral particle(Kaoline, clay, bentonite, dolomite, talc, silica, sand) and vegetable powder(shrubs).
The additive that may be used in the fungicidal composition of the present invention includes an emulsifier, adhesive, dispersion agent or permeating agent. e.g., nonionic, anionic or cationic interface active agent(fatty acid sodium salt, polyoxy alkyl ester, alkyl sulfonate ester). Further, an agrochemically active ingredient, e.g., an insecticide, herbicide, plant growth regulator, germicide, and fertilizer, may be added in the composition of the present invention.